Editorial

A great deal is known about the human immunodeficiency virus (HIV) that causes acquired
immune deficiency syndrome (AIDS) [1], one of whose cardinal features is its exquisite adaptation to its human host. It
enters the body through damaged epithelia, or more insidiously, through specialized
cells (M cells) in the intestinal epithelium whose function is to deliver viruses
and bacteria to waiting immune cells in the tissue below. There, the virus binds to
a specialized receptor on the surface of one of these cells - the dendritic cells,
which play a central part in activating the CD4+ T lymphocytes whose destruction by the virus ultimately and lethally disables the
immune system. Recognition of the bound virus causes the dendritic cell to migrate
to the lymphoid tissues where it engages with the CD4+ T lymphocytes that it activates. This enables the virus to bind to molecules on the
surface of the T cell - a highly specific interaction involving the CD4 molecules
that give CD4+ T cells their name and that enables the virus to enter the cell. Once the virus is
inside the cell, it produces DNA copies of its genome that integrate into the host
DNA where cellular transcriptional regulators specifically induced by activation of
CD4+ T cells are instrumental in activating transcription of the viral genome to produce
more viruses.

A great deal is unknown about what happens to the adaptive immune system in consequence
of this fiendish and focused assault. The adaptive immune system consists of the lymphocytes
that provide lasting immunity, and CD4+ T lymphocytes are essential to activating most of adaptive immunity. The loss of
these cells in HIV infection thus punches an enormous hole in the immune defences
of the host. But CD4+ T cells are homeostatically self-renewing, and it is still unclear exactly why they
are progressively lost in HIV infection. It is also unclear what happens to the dynamics
of the immune system. HIV infection, paradoxically, is characterized by generalized
immune activation the basis for which is not understood. These lacunae in understanding
are due at least partly to limitations to the research tools available to investigate
these phenomena.

Because of its intimate and specific dependence on the host cell machinery, HIV infects
only humans, although there is a monkey counterpart, SIV, that produces a syndrome
similar to AIDS in rhesus macaques. (Rhesus macaques are not the natural host of SIV:
in sooty mangabeys, which are, it causes little inconvenience - another phenomenon
that is not understood.) So AIDS can be investigated only in humans and monkeys, which
are cumbersome and limited experimental tools. Mice, whose immune systems are the
best-understood in the animal kingdom and which offer ease of maintenance and manipulation,
have no equivalent pathogen.

With this in mind, George Kassiotis and colleagues set out to generate a mouse in
which, as in human HIV infection, CD4+ T cells are killed on activation. They did this by a feat of genetic engineering
involving Cre-lox and the A fragment of diphtheria toxin (DTA) and which is described
both in their paper in this issue of Journal of Biology [2] and, more succinctly, in the accompanying commentary [3]. Investigation of the engineered mouse has led them to the conclusion that at least
some of the disturbance to immune dynamics in HIV infection may be due to the preferential
destruction of a highly topical and much-invoked subset of CD4+ T cells called regulatory T cells. In the accompanying commentary, Nienke Vrisekoop,
Judith Mandl and Ronald Germain explain what is known and what is not known about
immune dynamics in HIV infection, where the mouse results are and are not consistent
with what we know, and what the value of this tool may be.

One way or another, the CD4+ T cell conditional mutant mouse may help to close the gap between the detailed understanding
of the molecular and cell biology of HIV infection, and the very imperfect understanding
of the impact of HIV on T cell dynamics.